Introduction
Multiple myeloma (MM) is a hematological malignancy that represents approximately 1% of all cancers and around 10% of hematologic malignancies [ 1 ]. The exact cause of MM is unknown, but it is associated with cytogenetic mutations in the plasma cell allowing it to divide uncontrollably [ 2 ] and build up in the bone marrow, where it may prevent normal blood cells from developing. The resulting clonal plasma cells usually release 1 specific type of immunoglobulin denoted a monoclonal immunoglobulin (M-protein), which can be measured in the blood and is used as a marker of the disease. The clonal plasma cells can have different cytogenetic abnormalities, some of which are included in risk stratification of the disease [ 3 , 4 ].
The clinical manifestations, which also serve as an important tool in the diagnosis of MM, are commonly summarized by the acronym "CRAB": calcium elevation; renal insufficiency; anemia; and bone disease - most commonly lytic lesions evidenced by imaging [ 4 ].
Extramedullary manifestations of MM are rare and generally indicate advanced disease. Involvement of the central nervous system (CNS-MM) is exceedingly uncommon and carries a poor prognosis despite multimodal treatment [ [5] , [6] , [7] , [8] ].
This case report describes the relapse of IgA lambda MM in a patient previously in stringent complete remission (sCR), who presented with extensive extramedullary disease, including signs of CNS involvement consisting of abnormal thickness and contrast enhancement of the pituitary stalk and signs suggestive of cerebral venous sinus thrombosis (CVST) detected with magnetic resonance imaging (MRI).
Case report
A 67-year-old female with IgA lambda MM, characterized by high-risk cytogenetic abnormalities and osteolytic bone lesions, achieved sCR following first-line standard therapy, which included induction treatment with bortezomib-lenalidomide-dexamethasone and tandem autologous stem cell transplantation. She subsequently received lenalidomide maintenance, which was ongoing when she was admitted to our hospital with persistent shortness of breath, retrosternal pain, and dysphagia.
A biochemical evaluation revealed elevated D-dimer and slightly increased troponin. After ruling out acute coronary syndrome and given the patient's increased risk for pulmonary embolism (PE) due to malignant disease as well as lenalidomide treatment, a CT-angiography was performed. Imaging ruled out PE and revealed an infiltrative process in the posterior mediastinum, with concomitant bilateral pleural masses and moderate pleural effusion on the right side. The patient was subjected to further diagnostic evaluation in accordance with the local clinical guidelines for suspected lung cancer.
¹⁸F-FDG-PET/CT revealed pathological FDG uptake in the mediastinal tumor, in bilateral pleural masses, in multiple bone lesions, as well as in a sub-solid lesion in the right lower lobe.
Cytological and histological examination of the mediastinal mass, obtained via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), revealed numerous plasmablastic plasma cells with lambda light chain restriction. Immunohistochemistry was positive for CD138, CD38, and MUM1, with variable CD56 expression. Blood analysis showed no detectable M-protein and only slight elevation of the lambda light chains. A subsequent bone marrow biopsy showed no evidence of clonal plasma cells. Collectively, these findings were consistent with a non-secretory relapse of MM with extramedullary disease.
As per local guidelines, a contrast-enhanced brain MRI was performed, revealing abnormal findings suggestive of CNS involvement. To better characterize these abnormalities, a contrast-enhanced MRI of the hypophysis was subsequently performed, which demonstrated thickening of the infundibular stalk up to 6 mm, with heterogeneous contrast enhancement, findings considered consistent with, and further raised suspicion for, CNS involvement CNS involvement ( Fig. 1 ). The pituitary gland itself appeared normal, with no pathological findings. Furthermore, there was no radiological evidence of intracerebral metastases or meningeal infiltration. Additionally, MRI demonstrated absence of normal flow void in the superior sagittal sinus, as well as increased signal intensity on T1-weighted and FLAIR sequences, and lack of contrast enhancement ( Fig. 2 ), consistent with CVST. Diffusion-weighted imaging showed no restricted diffusion. On susceptibility-weighted imaging, no evidence of parenchymal hemorrhage or calcification was detected. Fig. 1 (A) Sagittal T1-weighted FLAIR gadolinium-enhanced sequence demonstrating abnormal contrast enhancement of the pituitary stalk. (B) Coronal T1-weighted gadolinium-enhanced sequence showing a thickened pituitary stalk with heterogeneous contrast enhancement. Fig 1 – Fig. 2 (A, B) Sagittal FLAIR and axial T2 image showing absence of flow void and increased signal intensity in the superior sagittal sinus (arrow) (C) Contrasted-enhanced axial T1 sequence showing contrast filling defects in the superior sagittal sinus (arrow). Images are suggestive of CVST. Fig 2 –
The findings revealed probable CNS involvement of MM. At the time, the working diagnosis was assumed lymphocytic hypophysitis, which was assumed to be the most likely explanation for the observed findings. Consequently, no cerebrospinal fluid (CSF) analysis or MRI angiography was undertaken to further investigate other causes. As a result, cytologic confirmation of CNS-MM is lacking.
An intensive relapse regimen consisting of daratumumab, doxorubicin, cyclophosphamide, and bortezomib was initiated. Of these agents, cyclophosphamide penetrates the blood brain barrier well, whereas the rest have poor CNS penetration. Despite normalization of light chains, the patient demonstrated a mixed metabolic response on evaluative PET/CT. Consequently, treatment was switched to carfilzomib, pomalidomide, and dexamethasone. Of these agents pomalidomide showed good CNS penetration, but despite treatment changes disease progression continued. Ultimately, teclistamab was introduced as fourth-line therapy for the aggressive disease. At the time the treatment was administered, this was considered a novel therapy; however, its CNS penetration is still uncertain and likely limited [ 9 ]. Despite multiple treatment regimens, the disease progressed rapidly.
Follow-up CT imaging of the thorax, abdomen, and brain revealed disease progression with appearance of an extracranial soft tissue mass, calvarial lytic lesions, and extensive tumor infiltration involving the right pleura, thoracic wall, pericardium, and adjacent musculature. A repeat brain MRI 3 months after relapse showed unchanged findings from the initial MRI scan. Initial endocrine labs were normal, however, subsequent testing demonstrated decreased cortisol (34 nmol/L) and corticotropin (<1.11 mmol/L), suggesting hypopituitarism. Planned follow-up MRI and endocrine evaluations, including an ACTH stimulation test, were postponed multiple times and ultimately canceled by the patient herself, due to deteriorating clinical condition.
Given the patient’s poor prognosis and progressive decline despite a rather intensive treatment, the disease was deemed terminal, and she was transitioned to palliative care with supportive management. The patient passed away approximately 7 months after relapse was first diagnosed.
Discussion
The diagnostic evaluation of MM includes a comprehensive integration of laboratory, histopathological, and imaging findings to confirm clonal plasma cell proliferation, assess disease burden, and identify myeloma-defining events. Current International Myeloma Working Group (IMWG) recommendations favor cross-sectional imaging, including CT, MRI and ¹⁸F-FDG PET/CT, over conventional skeletal surveys, as these modalities are significantly more sensitive for detecting early bone lesions and extramedullary disease [ 10 , 11 ]. Among these, whole-body CT is recommended as the primary imaging method to identify osteolytic lesions. ¹⁸F-FDG PET/CT can be used in place of whole-body CT if necessary and is currently the preferred imaging method to create a baseline for response assessment [ 11 ]. MRI is considered the most sensitive imaging technique for detecting bone marrow and CNS involvement [ 6 , [10] , [11] , [12] ] and, in case whole body CT is negative and other myeloma defining events (MDE) are absent, whole-body MRI is recommended as the next diagnostic step [ 11 ].
Diagnosis of CNS-MM can be challenging. This condition may occur either through direct extension from adjacent bone lesions or via hematogenous dissemination, resulting in parenchymal infiltration, dural-based masses, or leptomeningeal disease [ 12 ]. Consequently, imaging findings are heterogeneous and often non-specific, ranging from diffuse leptomeningeal enhancement to discrete parenchymal or dural lesions [ 8 ]. MRI, either alone or combined with CSF analysis, has an estimated sensitivity of up to 90% for detecting CNS manifestations of MM [ 6 ]. While CSF cytology and flow cytometry are frequently used to diagnose CNS-MM [ 13 , 14 ], these procedures are frequently limited in clinical practice, particularly in advanced or rapidly progressive disease where patient performance status or palliative intent precludes invasive testing [ 8 ]. In such situations, further diagnostic workup (eg, endocrine testing or repeat imaging) may be limited by rapid clinical deterioration and ongoing systemic therapy, including corticosteroids and doxorubicin treatment, which may also complicate endocrine evaluation. Diagnosis of CNS-MM often relies therefore on a combination of imaging features, clinical context, and disease chronology for establishing a probable diagnosis and guiding management decisions.
In the present patient, the MRI findings raised suspicion of both CNS involvement by MM and CVST. Although not pathognomonic, their temporal association with systemic relapse in a patient previously in sCR strongly supports probable secondary CNS involvement. However, in the context of absent histological confirmation as well as absence of MR venography and cancellation of the follow-up examinations by the patient, differential diagnoses must be acknowledged. The MRI pattern of pituitary stalk involvement can be seen in inflammatory, infectious, granulomatous, or metastatic conditions, including craniopharyngioma, Langerhans cell histiocytosis, lymphocytic hypophysitis, and paraneoplastic syndromes. Each of these conditions may require distinct therapy (eg, corticosteroids or immunosuppressants for hypophysitis, antimicrobial therapy for infections, surgery/radiotherapy for tumors) [ 15 ].
The observed superior sagittal sinus abnormality can be either disease-related or an iatrogenic thrombotic event. MM is a well-recognized prothrombotic condition, and prolonged lenalidomide therapy, which was used for maintenance in this patient during the remission period, further increases the risk of venous thromboembolism. A similar case of CVST in MM associated with lenalidomide has been reported [ 16 ]. Nonetheless, the previous absence of classical CNS symptoms such as headache or seizures, commonly associated with CVST [ 17 ], combined with the timing of relapse and radiologic progression, favors a disease-related rather than treatment-induced thrombosis.
In this patient, CNS-MM remains a probable rather than proven diagnosis. The disease course was fulminant, with rapid systemic and persistent CNS involvement despite multiple lines of therapy, including agents with known CNS penetration. This pattern is consistent with prior reports, where CNS involvement typically emerges at relapse and carries an extremely poor prognosis, with median survival of only a few months despite intensive multimodal treatment [ [5] , [6] , [7] , [8] ].
Conclusion
This case illustrates the diagnostic challenges of suspected CNS involvement in MM, in which imaging findings suggested CNS-MM but histopathologic confirmation was not achievable due to the patient’s rapid clinical deterioration. It highlights how, in such aggressive and advanced presentations, diagnosis often relies on integrating imaging and clinical data rather than definitive proof. CNS-MM diagnosis is challenging, and the nonspecific nature of imaging and overlap with inflammatory, infectious, or metastatic conditions further complicate assessment.
Reporting these cases remains crucial to raise awareness of CNS-MM’s complex diagnosis and to highlight the importance of timely recognition and multidisciplinary assessment in improving patient care.
Patient consent
Written informed consent was obtained from the patient for publication of this case report.
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Competing Interests: The authors have declared that no competing interests exist.